1. Field of the Invention
The invention relates to microporous thermoplastic foams and polymeric articles with microporous surface layers and methods for preparing these foams and articles. More specifically, the invention provides a method for producing foams with controlled pore size, chemical reactivity and mechanical properties, as well as microporous surfaces with modulated porosity, lyophilicity and chemical reactivity that may be utilized in a variety of applications, including drug delivery systems, constructs for bone and cartilage regeneration, constructs for organ generation, filters for protein fractionation, matrices for gas and fluid filtration, templates for three-dimensional cell cultures, bioreactor substrate material constructs containing immobilized chemical and biological reagents for use in continuous chemical and biochemical processing, and the like.
2. Description of the Related Art
It is expected that there are many potential biomedical applications for microcellular foams although not necessarily disclosed in the prior art. Among the potential uses are, use as timed-release drug delivery systems, neural regeneration pathways, templates for skin generation/regeneration, vascular replacements and artificial bone templates. Specific areas of immediate biomedical significance include use of absorbable microcellular foams for bone and cartilage regeneration applications as well as the use of microcellular foams for organ generation, components of bioreactor cartridges, such as those useful for the production of growth factors, microcellular filters for protein fractionation, microcellular matrices for gas and fluid filtration, and microcellular constructs containing immobilized chemical and biological reagents, as well as living cells, for use in continuous chemical and biochemical processing. Some of these applications are discussed in the patent literature.
For instance, U.S. Pat. Nos. 4,902,456 and 4,906,377 discuss the manufacture of fluorocarbon porous films from poly(tetrafluoroethylene-co-perfluoroalkyl vinyl ether) (PFA) or poly(tetrafluoroethylene-co-hexafluoropropylene) (FEP). The porous films are permeable to both liquids and gases and can be used as filtration media. In producing the films, a mixture is formed. The mixture includes between about 10 to about 35 wt. % FEP or PFA polymer with the remainder being a solvent (porogen) chlorotrifluorethylene oligomer which permits liquid-liquid phase separation upon cooling from elevated temperature and subsequent solidification of the polymer. The mixture is heated and extruded to form a film or hollow fibers which are then quenched to effect phase separation of the fluorocarbon polymer from the solvent. The extrudate is quenched by passing it over a chill roller which cools the extrudate to a temperature that causes microphase separation of polymer and solvent. The solvent is separated from the polymer by extraction and the resultant microporous polymeric membrane is dried under restraint in order to minimize or prevent membrane shrinkage and collapse.
U.S. Pat. No. 4,603,076 relates to hydrophilic flexible foams that are said to be particularly suited for use in external biomedical applications. The polyurethane films are produced by blowing a methylene diphenyl diisocyanate (MDI) prepolymer with a substantially non-aqueous blowing agent, such as pressurized air. The prepolymer is then polymerized with polyoxyethylene polyol having at least two hydroxyl equivalents per mole. The hydrophilic foam may be extruded, knife coated, or cast into sheets.
Likewise, U.S. Pat. No. 5,071,704 relates to specific foams into which a reservoir layer may be incorporated for allowing controlled release of vapors or liquids of an active compound into the surrounding environment. This is accomplished by incorporating a diffusion rate-limiting membrane layer, into a laminate of the foam, which controls the rate at which the active compound diffuses to the surface of the laminate and vaporizes or dissolves into the environment.
U.S. Pat. No. 5,098,621 relates to flexible foam substrates for selectively releasing and dispensing active ingredients. The composite material includes an open foam substrate containing particles of micropackaged active ingredient liquids or solids, formed with frangible containment walls, for breaking and releasing active ingredients in response to a defined level of stress.
Whereas the above patents indicate methods for making foams, microcellular foams made from biomedically significant polymers are of particular interest. Further, production of polymeric microporous foams having continuous cellular structures has not been exploited to any great extent. Microcellular foams have been produced using various materials and processes, but these foams cannot be produced from biomedically useful polymers, in high quality, uniform structures, using the two traditional methods: low temperature freeze drying and salt leaching, or the more recent technique, thermally induced phase separation (TIPS). Salt leaching has several limitations including the fact that it is often difficult to form small micropores with salt and it requires a high salt loading to achieve interpore channeling to produce continuous microporous foams. Further, there is a limited availability of solvents for polymers intended for biomedical use. Freeze drying also has its limitations. Specifically, there is a limited availability of crystallizable solvents that can be sublimed at the low temperatures characteristic of the freeze drying process. Further, the freeze drying process is a batch process which imposes limitations in terms of the size and shape of the foam produced.
Thermally Induced Phase Separation (TIPS) is a general process for forming cellular foams. A requirement of this process is that the polymer must be diluted with leachable, low molecular weight organic compounds without experiencing chemical degradation of the polymer chain molecule. Provisions of the TIPS method are that (a) a one-phase polymer-diluent system is cooled to effect phase separation; (b) bicontinuous phases (i.e. two phases completely intermingled with the architecture of a filled foam) are to be maintained before the polymer undergoes vitrification or crystallization; and (c) removal of the diluent does not partially or fully collapse the bicontinuous morphology.
Three types of TIPS have been described in the literature, namely liquid-liquid phase separation, liquid-solid phase separation, and solid-liquid phase separation. In each type of phase separation, the first adjective describes the polymer and the second describes the diluent.
Liquid-liquid phase separation occurs when, upon cooling, the polymer and diluent phase separate prior to solidification of either phase. Liquid-liquid phase separation can be further divided into two types of differing kinetics. One type of liquid-liquid phase separation occurs in the nucleated region which is between the binodal and spinodal boundaries of a polymer-diluent temperature-composition phase diagram. The other type of liquid-liquid phase separation occurs below the spinodal boundary in the region of spinodal decomposition. The nucleated region is characterized by phase separation induced by the nucleation of a second phase. The maxima of the spinodal boundary is the critical point of the polymer/solvent system. To one side of the critical point, the nucleated phase is polymer-rich while it is solvent-rich to the other side. In each case, the energy associated with the interfacial area determines the critical size of the nuclei. Therefore, nucleation occurs following a characteristic lag time during which nuclei grow to a sufficient size for stability.
Liquid-solid phase separation occurs when the diluent solidifies prior to polymer crystallization. Solid-liquid phase separation involves solidification of the polymer prior to diluent solidification.
These methods, liquid-liquid, liquid-solid and solid-liquid, provide cellular structures with irregular morphologies that are highly dependent on concentration of the polymer, polymer-diluent interaction and cooling rate. For the liquid-liquid case, full maintenance of the bicontinuous morphology is essentially unachievable Therefore, an irregular, rather than highly uniform, cellular structure is realized. A relatively more uniform, in comparison to foams prepared using liquid-liquid TIPS, but still irregular foam morphology can be achieved with liquid-solid and solid-liquid systems, provided that fast cooling rates (or quenching) prevail. Fast cooling rates are required (a) to minimize spherulitic growth of the crystallizing polymer in a solid-liquid system and (b) to allow the diluent to crystallize in the presence of a super-cooled polymer in a liquid-solid system.
TIPS, in concert with low-temperature freeze-drying technology, has been used to produce microcellular foams made of dextran, cellulose and polystyrene. Limitations associated with available materials and solvents have generally restricted the growth of TIPS foam formation technology. In the TIPS process, the pore formation is preceded by a liquid-liquid, liquid-solid or solid-liquid phase separation that is difficult to control. Further, the TIPS process requires solidifying the solvent-polymer mixture with rapid cryogenic quenching. This type of quenching presents an obstacle to large scale manufacturing processes.
Production of microcellular foams with controlled chemical and mechanical properties and morphology would facilitate the use of biologically safe polymers for the production of microcellular foams for biomedical applications. The growing demand for polymeric microcellular foams in several areas of advanced technology represent an urgent need for developing a method for converting non-bioabsorbable and bioabsorbable polymers, which cannot be processed in a traditional manner, to microcellular foams.
There exists a need for a continuous, open-cell microcellular foam and a process for producing such a foam on a typical manufacturing scale from organic polymers suitable for biomedical applications, without the need for complex new equipment to make the foams. Further, the process should be readily applicable to a broad range of thermoplastic polymers which can be absorbable or non-absorbable. Representative non-absorbable polymers include, but are not limited to, polyamides, aromatic polyesters and polyolefins, while the absorbable type of polymers can be based totally or partially on polymers such as polylactic acid, polyglycolic acid, polyalkylene oxalate, polydioxanone and polyanhydride. Further, the process should allow some measure of control of the size of the open-cell pores or voids so that foams may be custom tailored for particular applications, such as timed-release drug delivery systems, constructs for regeneration of bone, cartilage and a multiplicity of soft tissues (including skin and liver), constructs for organ generation, filters for protein fractionation, matrices for gas and fluid filtration, constructs for use in bioreactor cartridges used for continuous chemical and biochemical processing, and the like. The inner and outer microporous cell surfaces can be chemically activated to allow the creation of chemically active functionalities which can be used to bind biologically active agents ionically or covalently.